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Detection of M. tuberculosis DNA in CD34-Positive Peripheral Blood Mononuclear Cells of Asymptomatic TB Contacts

29 Pages Posted: 29 Feb 2020

See all articles by Mulugeta Belay

Mulugeta Belay

Queen Mary University of London - Barts and The London School of Medicine and Dentistry

Begna Tulu

Addis Ababa University

Sidra Younis

Queen Mary University of London - Barts and The London School of Medicine and Dentistry

David A. Jolliffe

Queen Mary University of London - Institute of Population Health Sciences

Dawit Tayachew

Armauer Hansen Research Institute

Hana Manwandu

Armauer Hansen Research Institute

Tenagne Abozen

Armauer Hansen Research Institute

Emawayish A. Tirfie

Armauer Hansen Research Institute

Metasebia Tegegn

Armauer Hansen Research Institute

Aboma Zewude

National University of Medical Sciences

Sally Forrest

University of Cambridge

Jonathan Mayito

Makerere University - School of Biomedical Sciences

Jim F. Huggett

LGC

Gerwyn Jones

LGC

Denise M. O’Sullivan

LGC

Henny M. Martineau

University of London - Royal Veterinary College

Mahdad Noursadeghi

University College London - Division of Infection and Immunity

Aneesh Chandran

University College London - Division of Infection and Immunity

Kathryn A. Harris

Great Ormond Street Hospital for Children

Vlad Nikolayevskyy

Government of the United Kingdom - Public Health England

Julie Demaret

Centre de Biologie-Pathologie-Génétique du CHRU de Lille

Stefan Berg

Animal and Plant Health Agency

Martin Vordermeier

Animal and Plant Health Agency

Taye T. Balcha

Lund University

Abraham Aseffa

Armauer Hansen Research Institute

Gobena Ameni

Addis Ababa University

Markos Abebe

Armauer Hansen Research Institute

Stephen T. Reece

University of Cambridge

Adrian R. Martineau

Queen Mary University of London - Barts and The London School of Medicine and Dentistry; Queen Mary University of London - Institute of Population Health Sciences; Queen Mary University of London - Asthma UK Centre for Applied Research

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Abstract

Background: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for M. tuberculosis complex (MTBC) bacilli during latent tuberculosis infection (LTBI).

Methods: We conducted a cross-sectional study in Ethiopia to determine whether MTBC DNA was detectable in peripheral blood mononuclear cells (PBMC) isolated from 100 ml blood taken from 197 asymptomatic adults with a history of recent household TB contact and/or HIV infection, using digital polymerase chain reaction (dPCR). A nested prospective study was conducted in a sub-set of 43 HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy (IPT) was effective in clearing MTBC DNA from PBMC.

Results: MTBC DNA was detected in PBMC of 156/197 participants (79.2%; 95% CI 73.5% to 84.9%). Where present, it was found more frequently in CD34-positive vs. CD34-negative PBMC (154/155 [99.4%] vs. 46/155 [29.7%], P<0.001). Prevalence of dPCR-detected MTBC DNA did not differ between QuantiFERON-negative vs. QuantiFERON-positive participants (77/99 [77.8%] vs. 79/98 [80.6%], P=0.73), but it was higher in HIV-infected vs. HIV-uninfected participants (67/75 [89.3%] vs. 89/122 [73.0%], P=0.006). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected vs. HIV-uninfected participants (25/75 [33.3%] vs. 73/122 [59.8%], P<0.001). Administration of IPT reduced prevalence of dPCR-detected MTBC DNA from 41/43 (95.3%) at baseline to 23/43 (53.5%) post-treatment (P<0.001), but it did not influence prevalence of QuantiFERON-positivity (17/43 [39.5%] at baseline vs. 13/43 [30.2%] post-treatment; P=0.13).

Conclusions: We report a novel molecular microbiological biomarker of LTBI with properties that are distinct from those of a commercial interferon-gamma release assay. Our findings implicate the bone marrow as a niche for M. tuberculosis in latently infected individuals. Detection of MTBC DNA in PBMC has potential applications in the diagnosis of LTBI, in monitoring response to chemoprophylaxis and as an outcome measure in clinical trials of interventions to prevent or treat LTBI.

Funding Statement: This work was supported by a grant from the United Kingdom Medical Research Council (Reference Number MR/P024548/1, to ARM). SF and STR acknowledge support from the Cambridge NIMR BRC antibiotic resistance theme. JM acknowledges support from the DELTAS Africa Initiative (ref DEL-15-011, via THRiVE-2). JFH, GJ and DMO’S acknowledge support from the UK government Department for Business, Energy & Industrial Strategy (BEIS).

Declaration of Interests: STR has a pending patent that is relevant to the work. All other authors have no competing interests to declare.

Ethics Approval Statement: The study was approved by the Ethiopian National Research Ethics Review Committee, Addis Ababa, Ethiopia (ref 310/253/2017). Written informed consent was obtained from all participants.

Keywords: Latent tuberculosis infection; haematopoietic stem cell; digital polymerase chain reaction; IS6110; rpoB; ESAT6; biomarkers

Suggested Citation

Belay, Mulugeta and Tulu, Begna and Younis, Sidra and Jolliffe, David A. and Tayachew, Dawit and Manwandu, Hana and Abozen, Tenagne and Tirfie, Emawayish A. and Tegegn, Metasebia and Zewude, Aboma and Forrest, Sally and Mayito, Jonathan and Huggett, Jim F. and Jones, Gerwyn and O’Sullivan, Denise M. and Martineau, Henny M. and Noursadeghi, Mahdad and Chandran, Aneesh and Harris, Kathryn A. and Nikolayevskyy, Vlad and Demaret, Julie and Berg, Stefan and Vordermeier, Martin and Balcha, Taye T. and Aseffa, Abraham and Ameni, Gobena and Abebe, Markos and Reece, Stephen T. and Martineau, Adrian R., Detection of M. tuberculosis DNA in CD34-Positive Peripheral Blood Mononuclear Cells of Asymptomatic TB Contacts (February 17, 2020). Available at SSRN: https://ssrn.com/abstract=3539684 or http://dx.doi.org/10.2139/ssrn.3539684

Mulugeta Belay

Queen Mary University of London - Barts and The London School of Medicine and Dentistry

London, EC1M 6BQ
United Kingdom

Begna Tulu

Addis Ababa University

King George VI St
Addis Ababa, 1000
Ethiopia

Sidra Younis

Queen Mary University of London - Barts and The London School of Medicine and Dentistry

London, EC1M 6BQ
United Kingdom

David A. Jolliffe

Queen Mary University of London - Institute of Population Health Sciences

London
United Kingdom

Dawit Tayachew

Armauer Hansen Research Institute

Ethiopia

Hana Manwandu

Armauer Hansen Research Institute

Ethiopia

Tenagne Abozen

Armauer Hansen Research Institute

Ethiopia

Emawayish A. Tirfie

Armauer Hansen Research Institute

Ethiopia

Metasebia Tegegn

Armauer Hansen Research Institute

Ethiopia

Aboma Zewude

National University of Medical Sciences

Pakistan

Sally Forrest

University of Cambridge

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Jonathan Mayito

Makerere University - School of Biomedical Sciences

P.O Box 7062
Kampala
Uganda

Jim F. Huggett

LGC

Middlesex
United Kingdom

Gerwyn Jones

LGC

Middlesex
United Kingdom

Denise M. O’Sullivan

LGC

Middlesex
United Kingdom

Henny M. Martineau

University of London - Royal Veterinary College

Royal College St
Greater London, NW1 0TU
United Kingdom

Mahdad Noursadeghi

University College London - Division of Infection and Immunity

Gower Street
London, WC1E 6BT
United Kingdom

Aneesh Chandran

University College London - Division of Infection and Immunity

Gower Street
London, WC1E 6BT
United Kingdom

Kathryn A. Harris

Great Ormond Street Hospital for Children

London
United Kingdom

Vlad Nikolayevskyy

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

Julie Demaret

Centre de Biologie-Pathologie-Génétique du CHRU de Lille

Lille
France

Stefan Berg

Animal and Plant Health Agency

Surrey
United Kingdom

Martin Vordermeier

Animal and Plant Health Agency

Surrey
United Kingdom

Taye T. Balcha

Lund University

Box 117
Lund, SC Skane S221 00
Sweden

Abraham Aseffa

Armauer Hansen Research Institute

Ethiopia

Gobena Ameni

Addis Ababa University

King George VI St
Addis Ababa, 1000
Ethiopia

Markos Abebe

Armauer Hansen Research Institute

Ethiopia

Stephen T. Reece

University of Cambridge

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Adrian R. Martineau (Contact Author)

Queen Mary University of London - Barts and The London School of Medicine and Dentistry ( email )

Blizard Institute
4 Newark St.
London, E1 2AT
United Kingdom
+44 207 882 2551 (Phone)
+44 207 882 2552 (Fax)

Queen Mary University of London - Institute of Population Health Sciences ( email )

London
United Kingdom
+44 207 882 2551 (Phone)
+44 207 882 2552 (Fax)

Queen Mary University of London - Asthma UK Centre for Applied Research

London
United Kingdom

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